Anaphylaxis
F. Estelle R. Simons, MD, FRCPC Winnipeg, Manitoba, Canada
Anaphylaxis occurs commonly in community settings. The rate
of occurrence is increasing, especially in young people.
Understanding potential triggers, mechanisms, and patient-
specific risk factors for severity and fatality is the key to
performing appropriate risk assessment in those who have
previously experienced an acute anaphylactic episode. The
diagnosis of anaphylaxis is based primarily on clinical criteria
and is valid even if the results of laboratory tests, such as serum
total tryptase levels, are within normal limits. Positive skin test
results or increased serum specific IgE levels to potential
triggering allergens confirm sensitization but do not confirm the
diagnosis of anaphylaxis because asymptomatic sensitization is
common in the general population. Important patient-related
risk factors for severity and fatality include age, concomitant
diseases, and concurrent medications, as well as other less well-
defined factors, such as defects in mediator degradation
pathways, fever, acute infection, menses, emotional stress, and
disruption of routine. Prevention of anaphylaxis depends
primarily on optimal management of patient-related risk
factors, strict avoidance of confirmed relevant allergen or other
triggers, and, where indicated, immunomodulation (eg,
subcutaneous venom immunotherapy to prevent Hymenoptera
sting–triggered anaphylaxis, an underused, potentially curative
treatment). The benefits and risks of immunomodulation to
prevent food-triggered anaphylaxis are still being defined.
Epinephrine (adrenaline) is the medication of first choice in the
treatment of anaphylaxis. All patients at risk for recurrence in
the community should be equipped with 1 or more epinephrine
autoinjectors; a written, personalized anaphylaxis emergency
action plan; and up-to-date medical identification.
Improvements in the design of epinephrine autoinjectors will
help to optimize ease of use and safety. Randomized controlled
trials of pharmacologic agents, such as antihistamines and
glucocorticoids, are needed to strengthen the evidence base for
treatment of acute anaphylactic episodes. (J Allergy Clin
Immunol 2010;125:S161-81.)
Key words: Anaphylaxis, allergic reaction, mast cell, basophil, IgE,
FceRI, histamine, tryptase, food allergy, medication allergy, venom
allergy, epinephrine, adrenaline, H1-antihistamine
From the Department of Pediatrics & Child Health, Department of Immunology, Faculty
of Medicine, University of Manitoba.
Disclosure of potential conflict of interest: F. Estelle R. Simons receives research support
from the Canadian Institutes of Health Research, serves on the Dey Anaphylaxis
Advisory Board, Intelliject Anaphylaxis Advisory Board, ALK-Abello Anaphylaxis
Advisory Board, and Sciele Anaphylaxis Advisory Board, and is a Lincoln Medical
Consultant.
Received for publication November 4, 2009; revised December 22, 2009; accepted for
publication December 22, 2009.
Address for reprints: F. Estelle R. Simons, MD, FRCPC Room FE125, 820 Sherbrook St,
Winnipeg, Manitoba, Canada, R3A 1R9. E-mail: lmcniven@hsc.mb.ca.
0091-6749/$36.00
! 2010 American Academy of Allergy, Asthma & Immunology
doi:10.1016/j.jaci.2009.12.981
Abbreviations used
CNS: Central nervous system
COPD: Chronic obstructive pulmonary disease
CVD: Cardiovascular disease
NSAID: Nonsteroidal anti-inflammatory drug
OSCS: Oversulfated chondroitin sulfate
Siglec: Sialic acid-binding immunoglobulin-like lectin
This chapter focuses mainly on anaphylaxis in community
settings. It provides an overview of epidemiology, pathogenesis,
clinical diagnosis, confirmation of the triggers, and long-term
management, including prevention of recurrences and emergency
preparedness. It highlights recent advances published since the
review of anaphylaxis published in the 2008 Mini-Primer.1
Anaphylaxis is currently defined as a serious allergic reaction
that is rapid in onset and might cause death.2 The diagnosis is con-
sidered to be highly likely when any one of 3 clinical criteria is
fulfilled (Table I)2; the presence of reduced blood pressure or
shock is not necessarily required. The terms anaphylactoid or
pseudoanaphylaxis are no longer recommended for use.
EPIDEMIOLOGY
The lifetime prevalence of anaphylaxis from all triggers is
estimated to be 0.05% to 2%.3 The rate of occurrence appears to
be increasing, especially in young people.4-14 Accurate commu-
nity-based population estimates are difficult to obtain because
of underdiagnosis, underreporting, and miscoding, as well as
use of different definitions of anaphylaxis and different methods
of case ascertainment in the different populations studied.15-17
Representative studies of anaphylaxis from all triggers in the gen-
eral population are summarized in Table II.3-12
It is likely that anaphylaxis is underdiagnosed, especially if it is
a patient’s first episode, if there is a hidden or previously
unrecognized trigger, or if symptoms are mild, transient, or
both.15 Patients might not be able to describe their symptoms if
awareness, cognition, and judgment are impaired or if they are
dyspneic or becoming unconscious. The presence of itching,
flushing, hives, and/or angioedema is helpful in making the diag-
nosis; however, skin and mucosal symptoms and signs are absent
or unrecognized in 10% to 20% of all anaphylactic episodes. Hy-
potension sometimes goes undocumented, especially in infants
and young children.15
Underreporting and miscoding of anaphylaxis remain impor-
tant issues.15 Only 1% of emergency department visits for acute
systemic allergic reactions receive the diagnosis of anaphylaxis;
many are called acute allergic reactions, or acute hypersensitivity
reactions.16,17 In a recent nationally representative probability
sample from hospital emergency departments in the United
States, 57% of likely episodes of anaphylaxis to food did not re-
ceive an emergency department diagnosis of anaphylaxis.13
Death from anaphylaxis is considered rare8,14,18-23; however,
underreporting of fatalities likely occurs for a variety of reasons.
S161
S162 SIMONS J ALLERGY CLIN IMMUNOL
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TABLE I. Clinical criteria for diagnosing anaphylaxis

Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, and
swollen lips-tongue-uvula) AND at least 1 of the following:
A. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
B. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
A. Involvement of the skin–mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula)
B. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)
C. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
D. Persistent gastrointestinal symptoms (eg, cramping abdominal pain, vomiting)
3. Reduced BP after exposure to a known allergen for that patient (minutes to several hours):
A. Infants and children: low systolic BP (age-specific) or greater than 30% decrease in systolic BP*
B. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline
Adapted from reference 2.
BP, Blood pressure; PEF, peak expiratory flow.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg 1 [2 3 age]) from 1 to 10 years, and less than 90 mm Hg
from 11 to 17 years. Normal heart rate ranges from 80 to 140 beats/min at age 1 to 2 years, from 80 to 120 beats/min at age 3 years, and from 70 to 115 beats/min after age 3 years.
Infants and young children are more likely to have respiratory compromise than hypotension or shock.

These include incomplete clinical information, including lack of a
history of concomitant diseases, concurrent medications, and
drug or alcohol abuse, and absence of a detailed death scene in-
vestigation (eg, interview of witnesses).22 Initial symptoms and
signs in fatal episodes of anaphylaxis commonly include respira-
tory distress rather than circulatory collapse.21 The autopsy find-
ings might be nonspecific, and laboratory test results might be
within normal limits; however, this cannot be used to exclude
the diagnosis of anaphylaxis.20-22
PATHOGENESIS
Triggers of anaphylaxis
Triggers of anaphylaxis in the community are listed in
Table III.24-69 In many countries the most common food triggers
are peanut, tree nuts, shellfish, fish, milk, egg, and sesame24-26;
however, there are important geographic variations, and in some
countries other foods, such as chestnut, rice, buckwheat, or chick-
pea, predominate.27 Any food can potentially trigger anaphylaxis,
including previously unrecognized triggers, such as quinoa,28
dragon fruit,29 or some fresh red meats containing carbohydrates.30
Food triggers can be hidden (eg, substituted foods, cross-reacting
foods, and cross-contacting foods).26 Food triggers also include ad-
ditives, such as spices, vegetable gums, and colorants (eg, carmine
[cochineal])31; contaminants, such as dust mites32; and parasites,
such as the live seafish nematode Anisakis simplex.33
Medication-triggered anaphylaxis can occur in patients of any
age; however, it is particularly common in middle-aged and older
adults. Antibiotics, especially b-lactam antibiotics, and nonste-
roidal anti-inflammatory drugs (NSAIDs), including aspirin,
ibuprofen, and other agents, are often implicated, as are chemo-
therapeutic agents.24,25,34-40 Newly recognized medication trig-
gers include loperamide37; contaminants in medications, such as
oversulfated chondroitin sulfate (OSCS)-contaminated heparin38;
seemingly innocuous substances, such as vitamins and supple-
ments containing folic acid39; and herbal treatments.40 Periopera-
tive medications,41 iodinated contrast media42 and medical dyes
are becoming increasingly relevant triggers in community set-
tings. Biological agents that trigger anaphylaxis include monoclo-
nal antibodies (mAbs), such as cetuximab, infliximab, and
omalizumab,43-45 and allergens used in immunotherapy.46,47 Vac-
cines to prevent infectious diseases seldom trigger anaphylaxis. If
they do, the culprit is seldom the immunizing agent itself.48-51
Rather, it is likely to be a protein excipient, such as gelatin or
egg, or rarely another excipient, such as dextran.48,51
Venom from stinging insects (Order Hymenoptera, family
Apidae [eg, honeybees]; family Vespidae [eg, yellow jackets,
yellow hornets, white-faced hornets, and paper wasps]; and
family Formicidae [eg, ants])52-54 or, less commonly, saliva
from biting insects (flies, mosquitoes, ticks, kissing bugs, and cat-
erpillars) can trigger anaphylaxis.54-57
In health care settings ongoing efforts to prevent anaphylaxis
from natural rubber latex have been relatively successful; how-
ever, in the community anaphylaxis is still occasionally reported
after direct exposure to latex-containing gloves, condoms, rubber-
handled racquets, balloons, latex-padded play pits, infant paci-
fiers, and bottle nipples. It also potentially occurs after ingestion
of foods that cross-react with latex, such as banana, kiwi, papaya,
avocado, potato, and tomato.58
Occupational allergens,25 seminal fluid,59 and, rarely, inhaled al-
lergens, such as animal dander60 or grass pollen, can also trigger an-
aphylaxis; some systemic absorption of these allergens likely occurs.
In addition, nonimmune perturbations of mast cells and
basophils might lead to anaphylaxis. This potentially occurs after
exercise61,62 and/or exposure to cold air or water, heat, sunlight/
UV radiation, insect venom constituents,52,53 radiocontrast me-
dia,34,42 ethanol, and some medications, including opioids,
COX-1 inhibitors, and vancomycin.24,25,34 In patients with exer-
cise-induced anaphylaxis, food is a common cotrigger61; it is
hypothesized that in these patients, food-sensitized immune cells
are relatively innocuous until they are redistributed into the sys-
temic circulation from gut-associated deposits during exertion.62
Idiopathic anaphylaxis is diagnosed when no triggers can
be identified based on history, skin tests are negative, and serum
specific IgE levels are absent or undetectable. Before this
diagnosis is made, however, the possibility of a hidden
or previously unrecognized trigger should be ruled
out,24,28-30,32,33,37-40,57 and the patients should be evaluated for
mastocytosis and clonal mast cell disorders.63-67
Mechanisms
The underlying pathogenesis of human anaphylaxis commonly
involves an immunologic mechanism in which IgE is synthesized
J ALLERGY CLIN IMMUNOL SIMONS S163
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TABLE II. Epidemiology of anaphylaxis in the general population: All triggers

Author Date Description of study
4
Yocum et al 1999 Rochester Epidemiology Project, linked
indexed medical records of the general
population of Olmstead County, MN
Simons et al5 2002 Dispensing data for all injectable
epinephrine formulations over 5
consecutive years in a general
population of 1.15 million in which all
dispensings are recorded
Bohlke et al6 2004 Large health maintenance organization
in the United States, 1991-1997; cases
identified from automated database
using ICD-9 codes 995.0, 995.6,
995.4, and 999.4 plus medical records
review
Helbling et al7 2004 Investigated anaphylaxis with circulatory
symptoms during a 3-year period,
1996-1998, in Bern, Switzerland
(population, 940,000); allergy clinic
medical records were reviewed, and
emergency departments were
contacted to identify additional cases.
Lieberman et al3 2006 Panel convened to review major
epidemiologic studies of anaphylaxis
Poulos et al8 2007 Data on hospital admissions for
anaphylaxis were extracted for the
periods 1993-1994 to 2004-2005,
respectively.
Camargo et al9 2007 State-by-state dispensing data (filled
prescriptions, including refills) for
epinephrine autoinjectors in 2004 in
the United States
Decker et al10 2008 Population-based incidence study from
1990-2000 in the Rochester
Epidemiology Project (see Yocum
et al study above in this table)
Lin et al11 2008 Characterization of anaphylaxis
hospitalizations in New York state in
patients <20 years of age
Sheikh et al12 2008 Recorded incidence and lifetime
prevalence of anaphylaxis in England
were investigated by using
QRESEARCH, a national aggregated
primary health care database
containing the records of >9 million
patients.
This table summarizes selected publications during the past decade in which the rate of occurrence of anaphylaxis from all triggers in the general population was estimated. These
estimates vary because of different definitions of anaphylaxis, different methods of case ascertainment, and the different populations studied.
ED, Emergency department; ICD-9, International Classification of Diseases–Ninth Revision.
Key findings
During the years 1983-1987, the average
annual incidence rate was 21/100,000
person-years, and the most common
triggers were foods, medications, and
insect stings.
Of this defined general population,
0.95% had injectable epinephrine
dispensed for out-of-hospital
treatment.
The incidence rate was 10.5 anaphylactic
episodes per 100,000 person-years.
Two hundred twenty-six people had 246
episodes of life-threatening
anaphylaxis with cardiovascular
symptoms, for an incidence rate of
7.9-9.6/100,000 person-years.
There was a frequency estimate of 50 to
2,000 episodes/100,000 person-years
or a lifetime prevalence of 0.05% to
2%.
There was a continuous increase by 8.8%
per year in the incidence rate of ED
visits/hospitalizations for anaphylaxis
and a steep increase in hospitalizations
for food-triggered anaphylaxis in
children <5 years of age.
State-by-state variation: average was
5.71 EpiPens per 1,000 persons (range
from 2.7 in Hawaii to 11.8 in
Massachusetts).
Overall age- and sex-adjusted incidence
rate of 49.8/100,000 persons; the
annual incidence rate increased from
1990 to 2000.
During the study period, 1990-2006, the
anaphylaxis hospitalization rate
increased by more than 4-fold.
Age/sex standardized incidence of
anaphylaxis was 6.7/100,000 person-
years in 2001 and increased by 19% to
7.9/100,000 person-years in 2005;
lifetime age/sex standardized
prevalence of anaphylaxis was 50/
100,000 in 2001 and increased by 51%
to 71.5/100,000 in 2005.
Comments
Anaphylaxis frequently was not
recognized by patients or physicians.
Dispensing rates were highest in those
<17 years of age (1.44%) and lowest
in those !65 years of age (0.32%).
There was a male predominance to age
15 years and a female predominance
after age 15 years.
After review of the sample using the
additional ICD-9 codes 708.0, 708.9,
995.1, 995.3, and 695.1, the incidence
rate was estimated at 68.4 cases/
100,000 person-years.
There were 3 deaths, resulting in a case
fatality rate of 0.0001%.
The largest number of incident cases
were found in children and
adolescents.
In children, hospitalizations for food-
induced anaphylaxis were an
increasing concern.
Regional variation was also noted: the
rate was significantly higher in
northern states (except Alaska) than in
southern states.
Age-specific rates were highest for ages
0-19 years (70/100,000 person-years).
There was overall bimodal age
distribution, with peaks in the very
young and in teens.
Adrenaline prescribing increased by 97%
over this time.

in response to allergen exposure and becomes fixed to high-
affinity receptors for IgE (FceRI receptors) on the surface
membranes of mast cells and basophils (Fig 1).1,2,24,25,69-72 Ag-
gregation of receptor-bound IgE molecules occurs on re-exposure
to the allergen and results in cell activation and mediator
release.70-72 IgE also contributes to the intensity of anaphylaxis
by enhancing the expression of FceRI on mast cells and baso-
phils.70-72
Rarely, other immunologic mechanisms that do not involve
IgE are implicated in human anaphylaxis.73 IgG-mediated
S164 SIMONS J ALLERGY CLIN IMMUNOL
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TABLE III. Mechanisms and triggers of anaphylaxis in the community

Immunologic mechanisms (IgE dependent)
Foods, such as peanut, tree nut, shellfish, fish, milk, egg, sesame, and food additives*
Medications, such as b-lactam antibiotics and NSAIDs, and biological agents!
Venoms, such as stinging insects (Hymenoptera)
Natural rubber latex
Occupational allergens
Seminal fluid (prostate-specific antigen)
Inhalants, such as horse, hamster, and other animal danders and grass pollen (rare)
Radiocontrast media"
Immunologic mechanisms (IgE independent, formerly classified as anaphylactoid reactions)
Dextran, such as high-molecular-weight iron dextran!
Infliximab!
Radiocontrast media"
Nonimmunologic mechanisms
Physical factors, such as exercise,§ cold, heat, and sunlight/UV radiation
Ethanol
Medications, such as opioids!
Idiopathic anaphylaxis
Consider the possibility of hidden or previously unrecognized allergensjj
Consider the possibility of mastocytosis/clonal mast cell disorder
Adapted from references 24-69.
*Food additives include spices, vegetable gums, colorants (carmine/cochineal), monosodium glutamate, sulfites, papain, and contaminants.
!Medications can potentially trigger anaphylaxis through an IgE-dependent immunologic mechanism, an IgE-independent immunologic mechanism, or direct mast cell
stimulation. Biological agents include mAbs (eg, cetuximab and omalizumab), allergens, vaccines, and hormones (eg, progesterone).
"Radiocontrast media potentially trigger anaphylaxis through an IgE-dependent immunologic mechanism or through activation of complement.
§With or without a food or medication cotrigger.
jjIncludes foods, biting insect saliva, other venoms, medications, and biological agents. Save food or food label, insect or other relevant material, and save patient serum sample for
customized in vitro tests, such as measurement of allergen-specific IgE (see the text for further details).

anaphylaxis has been reported due to high molecular weight iron
dextran or infusion of chimeric, humanized, or human
therapeutic mAbs, such as infliximab.44,51 Complement-medi-
ated anaphylaxis occurs in association with hemodialysis,
OSCS-contaminated heparin,38 protamine neutralization of hep-
arin, liposomal drugs, or polyethylene glycols. Direct activation
of the innate immune system might also contribute to triggering
anaphylaxis.74
In addition, as noted previously, nonimmune activation of mast
cells and basophils occurs.24,25,34
A trigger can lead to anaphylaxis through more than 1 mech-
anism; for example, radiocontrast media can trigger anaphylaxis
through an immunologic IgE-dependent mechanism and through
direct mast cell activation.34,42 OSCS-contaminated heparin trig-
gers anaphylaxis through activation of the complement system,
leading to generation of kallikrein, bradykinin, and the comple-
ment protein-derived anaphylatoxins C3a and C5a; in addition,
factor XII and the coagulation system are involved.38,75
Regardless of the immunologic or nonimmunologic triggering
mechanisms and regardless of whether FceRI or other receptors,
such as G protein–coupled receptors or Toll-like receptors, are
activated, mast cells and basophils play an important role in
initiating and amplifying the acute allergic response. After IgE/
FceRI binding and receptor aggregation, multiple tyrosine ki-
nases, including Lyn, Syk, and Fyn, are activated and exert both
positive and negative regulation on the signal transduction
cascade.70,71,76 Calcium influx is the essential proximal intracel-
lular event leading to mast cell degranulation and is controlled by
both positive and negative regulation through calcium chan-
nels.70,77 Mast cells and basophils release preformed chemical
mediators of inflammation, including histamine, tryptase, carbox-
ypeptidase A, and proteoglycans.68,70,71,78,79 They also release
newly generated mediators, such as leukotrienes, prostaglandins,
and platelet-activating factor, and cytokines, such as IL-6, IL-33,
and TNF-a, which is a late-phase mediator, as well as a preformed
mediator.68,70,71,80-84 Sphingosine-1-phosphate is now recog-
nized as a circulating mediator in anaphylaxis, and in addition,
it acts as a signaling component within the mast cell.85 Once ac-
tivated, the mast cell response is regulated by the balance of pos-
itive and negative intracellular molecular events that extend
beyond the traditional kinases and phosphatases.
New discoveries in mast cell biology have the potential to
improve the diagnostic and therapeutic approach to human
anaphylaxis. For example, stem cell factor and its receptor Kit
are fundamentally important in IgE/antigen-induced mast cell
activation, and concurrent inhibition of Kit- and FceRI-mediated
signaling achieves coordinated suppression of human mast cell
activation.86 An orally effective compound has been identified that
binds to Syk, downregulates the interaction of Syk with some of its
macromolecular substrates, and inhibits FceRI-induced mast cell
degranulation in vitro and anaphylaxis in vivo.87 Inhibitory sialic
acid-binding immunoglobulin-like lectins (Siglecs) are expressed
on human mast cells, on which Siglec-8 engagement results in in-
hibition of FceRI-dependent mediator release without apoptosis.88
Anti-IgE antibody potentially plays a therapeutic role by depleting
free IgE, with consequent downregulation of FceRI on mast cells
and basophils and deflation of the intracellular activation signal
triggered by IgE/FceRI aggregation.89 Basophil involvement in
anaphylaxis will likely be further elucidated in the future because
a monoclonal antibody directed against pro–major basic protein
1 has been identified.90 The opening of the endothelial barrier
through endothelial Gq/G11-mediated signaling has been identi-
fied as a critically important process leading to symptoms of ana-
phylaxis in many body organ systems.91
There are few studies of the role of genetic factors in human
anaphylaxis. Investigations in this area might improve our
J ALLERGY CLIN IMMUNOL SIMONS S165
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FIG 1. Mechanisms underlying human anaphylaxis. Anaphylaxis is commonly mediated through an

immune IgE-dependent mechanism. Rarely, it occurs through another immune mechanism. Uncommonly,
it occurs through direct (nonimmune) activation of mast cells. Idiopathic anaphylaxis, currently a diagnosis
of exclusion, presents opportunities for identification of previously unrecognized triggers, elucidation of
pathophysiologic mechanisms, and identification of patients with mastocytosis or clonal mast cell
disorders.69

understanding of why anaphylaxis occurs in only a minority of
persons who are sensitized to an antigen and why episodes vary
greatly in severity from mild with spontaneous remission to
severe and fatal.92,93
Patient-specific risk factors for severity and fatality
Patients might be at increased risk of anaphylaxis severity and
fatality because of age, concomitant disease, concurrent medica-
tions, and other factors that are still being delineated (Table
IV).24,25,64-69,93-108
In infants anaphylaxis is sometimes hard to recognize because
they cannot describe their symptoms, and many of the signs of
anaphylaxis in infancy, such as flushing and dysphonia after a
crying spell, spitting up or loose stools after feeding, and loss of
sphincter control, are ubiquitous in the healthy state.94 Teenagers
and young adults are at increased risk of anaphylaxis triggered by
foods and possibly other agents because of inconsistent behaviors
with regard to avoiding their confirmed relevant triggers and car-
rying epinephrine autoinjectors.95 During pregnancy, anaphy-
laxis places the mother and especially the baby at high risk of
fatality or permanent central nervous system (CNS) damage. Dur-
ing the first, second, and third trimesters, potential triggers of an-
aphylaxis are similar to those in nonpregnant women. During
labor and delivery, the most common triggers are penicillins
and other b-lactam antibiotics given as prophylaxis against neo-
natal group B streptococcal infection.96 Elderly adults are at in-
creased risk of fatality in anaphylaxis because of concomitant
diseases, such as chronic obstructive pulmonary disease
(COPD), and cardiovascular diseases (CVDs) and the medica-
tions used to treat them.21,97-99
In patients of any age, diseases that impede prompt recognition
of triggers or symptoms potentially place patients at increased
risk of anaphylaxis.24,25,69,93 These include impaired vision or
hearing, neurologic disorders, psychiatric disorders (including
depression), autism spectrum disorder, developmental delay,24,69
and use of medications, such as first-generation H1-antihista-
mines (eg, diphenhydramine and chlorpheniramine), antidepres-
sants, or CNS-active chemicals, such as ethanol or recreational
drugs.24,69
Concomitant diseases, such as asthma or other chronic respi-
ratory diseases, especially if severe or uncontrolled,21,24,25,69 and
also CVDs97-99 and mastocytosis or clonal mast cell disor-
ders,64-67,100-103 are associated with increased risk of life-threat-
ening or fatal anaphylaxis. Severe allergic rhinitis and severe
eczema increase the risk of life-threatening anaphylaxis to
some foods.105 Concurrent medications, such as b-blockers
and angiotensin-converting enzyme inhibitors increase the
severity of anaphylaxis, and b-blockers potentially make
anaphylaxis more difficult to treat.24,25,98,99,103,105
In some patients severe or fatal anaphylactic episodes might be
associated with defects in mediator degradation pathways and
intracellular signaling pathways, as reflected, for example, in
increased baseline serum tryptase levels (which are strongly
associated with insect sting–triggered anaphylaxis),67,103 in-
creased baseline plasma histamine levels,104 low serum angioten-
sin-converting enzyme activity,105 and reduced platelet-activating
factor acetylhydrolase activity.80
Other concomitant factors reported to increase the risk of an
anaphylactic episode include exercise; exposure to extremes of
temperature or humidity or high pollen counts; foreign travel or
other disruption of routine; feeling unwell; fever; acute infection,
S166 SIMONS J ALLERGY CLIN IMMUNOL
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TABLE IV. Patient factors that increase risk of anaphylaxis severity and fatality
Age*
Infants: Underrecognition, underdiagnosis; no appropriate epinephrine auto-injector dose
Adolescents and young adults: [ Risk-taking behavior
Pregnancy: During labor and delivery, antibiotic prophylaxis against neonatal group B streptococcal infection is a common trigger
Elderly: [ Risk of fatality from medication and venom-triggered anaphylaxis
Comorbidities*
Asthma and other respiratory diseases, especially if severe or uncontrolled
CVDs, including hypertension
Mastocytosis! and clonal mast cell disorders!
Allergic rhinitis and eczema"
Depression and other psychiatric diseases (might impair recognition of symptoms)
Thyroid disease (some patients with idiopathic anaphylaxis)
Concurrent medication/chemical use*
Potentially affect recognition of anaphylaxis
Sedatives/hypnotics/antidepressants/ethanol/recreational drugs
Potentially increase anaphylaxis severity
b-Blockers and ACE inhibitors
Other factors*
Exercise
Acute infection, such as upper respiratory tract infection
Menses
Emotional stress
Occupation, such as beekeeping
Priming effect of recent previous anaphylactic episode
Increased baseline plasma histamine levels (hyperhistaminemia)
Increased baseline serum tryptase levels
Reduced level of PAF AH activity, leading to increased PAF levels
Reduced level of ACE activity, leading to increased bradykinin levels
Adapted from references 68, 69, and 94-108.
ACE, Angiotensin-converting enzyme; AH, acetylhydrolase; PAF, platelet-activating factor.
*In some patients several factors might need to be present concurrently for risk to be increased, such as an elderly person plus cardiovascular disease plus b-blocker medication.
In others concurrent triggers might be needed, such as food plus exercise.
!Suggested by increased baseline total tryptase levels.
"Atopic diseases are a risk factor for anaphylaxis triggered by food, exercise, and latex but not for anaphylaxis triggered by insect stings, b-lactam antibiotics, or insulin.

such as an upper respiratory tract infection; emotional stress;
menses (premenstrual and ovulatory phases); and/or ingestion of
NSAIDs or ethanol.20,32,61,62,106-108
ASSESSMENT OF PATIENTS WITH A HISTORY OF
ANAPHYLAXIS
Ideally, patients with a history of an acute anaphylactic episode
should be referred to an allergy/immunology specialist with
training and experience in risk assessment in anaphylaxis, includ-
ing confirmation of the diagnosis, verification of the triggers, and
evaluation of comorbidities and concurrent medications.
Clinical diagnosis of anaphylaxis
When patients are seen after an acute anaphylactic episode, the
history of the episode should be confirmed and relevant emer-
gency medical services and emergency department records
should be reviewed.24,25,68,69,93 The history should focus on recall
of exposure to potential triggering agents or events, the minutes or
hours elapsed between exposure and symptom onset, and the ev-
olution of symptoms and signs. Involvement of body organ sys-
tems varies among patients and even in the same patient from
one episode to another; however, review of anaphylaxis case se-
ries reveals some general patterns. Skin involvement is reported
in 80% to 90% of episodes, respiratory tract involvement in up
to 70%, gastrointestinal tract involvement in up to 45%, cardio-
vascular system involvement in up to 45%, and CNS involvement
in up to 15% (Table V).24,25,69,93
The differential diagnosis of anaphylaxis includes common
entities, such as acute generalized hives, acute asthma, syncope,
panic attack, aspiration of a foreign body, and cardiovascular or
neurologic events.24,25 Postprandial syndromes, such as pollen-
food syndrome and scombroidosis, also need to be considered, as
do excess endogenous histamine syndromes, such as mastocytosis;
flush syndromes, including perimenopausal flushing; nonorganic
diseases, such as vocal cord dysfunction; and other diagnostic en-
tities, some of which are rarely encountered (Table VI).24-26,32,33,63-
68,109,110
The differential diagnosis is age related to some extent. In
infants foreign body aspiration, congenital malformations of the
respiratory or gastrointestinal tracts, and apparent life-threatening
event/sudden infant death syndrome need to be considered.94 In
middle-aged and elderly adults myocardial infarction, pulmonary
embolus, and stroke are important considerations.21,25,97
Laboratory tests at the time of the acute
anaphylactic episode
In some patients the clinical diagnosis of anaphylaxis can be
confirmed by means of a blood test; for example, an increased
plasma histamine level or serum total tryptase level. These tests
are not specific for anaphylaxis (Table VII).24,25,68,78,79
Plasma histamine levels should optimally be measured 15 to 60
minutes after onset of symptoms of anaphylaxis. Special handling
of the blood sample is required. Histamine and its metabolite,
N-methylhistamine, can also be measured in a 24-hour urine
sample.68 Serum total tryptase levels should optimally be
J ALLERGY CLIN IMMUNOL SIMONS S167
VOLUME 125, NUMBER 2

TABLE V. Symptoms and signs of anaphylaxis

Cutaneous/subcutaneous/mucosal tissue
Flushing, pruritus, hives (urticaria), swelling, morbilliform rash, pilor erection
Periorbital pruritus, erythema and swelling, conjunctival erythema, tearing
Pruritus and swelling of lips, tongue, uvula/palate
Pruritus in the external auditory canals
Pruritus of genitalia, palms, soles
Respiratory
Nose: pruritus, congestion, rhinorrhea, sneezing
Larynx: pruritus and tightness in the throat, dysphonia and hoarseness, dry staccato cough, stridor, dysphagia
Lung: shortness of breath, chest tightness, deep cough, wheezing/bronchospasm (decreased peak expiratory flow)
Cyanosis
Gastrointestinal
Nausea, cramping abdominal pain, vomiting (stringy mucus), diarrhea
Cardiovascular
Chest pain, palpitations, tachycardia, bradycardia, or other dysrhythmia
Feeling faint, altered mental status, hypotension, loss of sphincter control, shock, cardiac arrest
CNS
Aura of impending doom, uneasiness, throbbing headache, dizziness, confusion, tunnel vision; in infants and children, sudden behavioral changes, such
as irritability, cessation of play, and clinging to parent
Other
Metallic taste in the mouth
Dysphagia
Uterine contractions in postpubertal female patients
Adapted from references 24, 25, 93, and 94. Sudden onset of symptoms and signs is characteristic of anaphylaxis.

measured from 15 minutes to 3 hours after onset of symptoms. No
special handling of the blood sample is required. The total tryp-
tase level is typically increased in patients with anaphylaxis trig-
gered by an injected medication or an insect sting and in those
with hypotension and shock but is less likely to be increased in
those with anaphylaxis triggered by food or in those who are nor-
motensive.68,78 Serial measurements of serum total tryptase and
comparison with baseline levels obtained after the acute episode
or available in stored serum might be more helpful than measure-
ment at a single point in time.68,78
Other biomarkers reported to be useful in confirming an acute
episode of anaphylaxis include serum mature b-tryptase; mast
cell carboxypeptidase A3; chymase; platelet-activating factor;
bradykinin; C-reactive protein; cytokines, such as IL-2, IL-6, IL-
10, IL-33, and TNF-receptor I; and urinary cysteinyl leukotriene
E4 and 9-a-11-b prostaglandin F2.68,72,80-84 Many studies of these
potential biomarkers have included appropriate control groups,
such as patients with severe acute asthma, but some have not. Bio-
markers are released at different times after activation of mast cells
and basophils, and patients experiencing anaphylaxis in commu-
nity settings arrive in emergency departments at different time in-
tervals after symptom onset; therefore measurement of a panel of
different biomarkers might be useful.68
Confirmation of the triggers of anaphylaxis
An important aspect of risk assessment in patients who have
experienced anaphylaxis in the community is confirmation of the
trigger or triggers identified through a detailed history of
antecedent exposures, so that the relevant specific trigger or
triggers can be avoided and recurrences of anaphylaxis can be
prevented (Table VIII).24-26,34,52,58,61,68,69,93,111 Skin tests should
be performed with validated instruments, techniques, and record-
ing systems, preferably at least 3 to 4 weeks after the anaphylactic
episode, to allow time for rearming of skin mast cells and recovery
of mast cell releasability.68 Measurement of allergen-specific IgE
levels by using a quantitative method can be performed at any
time during or after the acute anaphylactic episode; however, if
the blood sample is obtained during or shortly after the episode
from patients who have received intravenous fluid resuscitation,
levels can be falsely undetectable or low because of the dilutional
effect on circulating IgE. Negative tests for sensitization to a trigger
in a patient with a convincing history of anaphylaxis from that trig-
ger should be repeated weeks or months later. It is important to note
that both positive skin tests and increased specific IgE levels indicate
sensitization to the allergens tested but are not diagnostic of anaphy-
laxis or any other disease.24-26,34,52,58,68,69
If indicated, incremental challenge/provocation tests should be
conducted in appropriately equipped health care facilities by
professionals trained and experienced in patient selection, timing
of the challenge, use of challenge protocols, and diagnosing and
treating anaphylaxis. Before a challenge is performed, the
potential risks and benefits should be discussed with the patient
(or, for children, the caregivers) and documented in the medical
record.68,111
Assessment of patients with food-triggered anaphy-
laxis. Skin prick tests with foods that elicit a wheal of 3 mm
larger than that caused by the negative control (eg. saline) are
considered positive. Commercially available food allergen ex-
tracts do not contain standardized allergens. Some food allergens,
such as fruits and vegetables, are labile and degrade in glycerin-
ated extracts during manufacture and storage; therefore skin prick
tests with these allergens are often performed with fresh foods.
Intradermal tests to foods are contraindicated because of lack of
specificity (false-positive tests) and their potential for triggering
anaphylaxis.26,68,112 An exception to this might be use of intrader-
mal tests to assess sensitization to fresh meat containing the car-
bohydrate galactose-a-1,3-galactose.30
In food-sensitized patients specific IgE levels have predictive
values for positive (failed) or negative (passed) food challenge
S168 SIMONS J ALLERGY CLIN IMMUNOL
FEBRUARY 2010

TABLE VI. Differential diagnosis of anaphylaxis people who have no history of anaphylaxis. For example, 60% of
Common entities Nonorganic disease young people have a positive skin prick test to 1 or more foods,
Acute generalized hives Vocal cord dysfunction yet most of those with positive tests have never experienced
Acute asthma Munchausen syndromejj anaphylaxis from a food.114 In addition, although positive skin
Syncope (faint, vasovagal episode) tests and increased allergen-specific IgE levels correlate with
Panic attack an increased probability of clinical reactivity to specific foods,
Aspiration of a foreign body Shock the results of these tests do not necessarily correlate with the
Cardiovascular event (myocardial Hypovolemic
risk of future anaphylactic episodes or with the severity of
infarction, pulmonary embolus) Cardiogenic
such episodes.26,68
Neurologic event (seizure, stroke) Distributive (eg, spinal cord injury)
Septic (might involve all of the above) Oral food challenge testing was extensively reviewed in the
Journal in 2009.111 Patients with a convincing history of anaphy-
Postprandial syndromes Other laxis to a specific food and evidence of sensitization to that food
Pollen-food syndrome* Nonallergic angioedema should not undergo oral food challenge tests because of their high
Scombroidosis! Red Man syndrome (vancomycin) risk of anaphylaxis from such tests. Others, such as those with an
Monosodium glutamate Urticarial vasculitis equivocal history, low or moderate evidence of sensitization, or
Sulfites Hyper-IgE urticaria syndrome
both, might benefit from a physician-monitored incremental
Progesterone anaphylaxis
Pheochromocytoma
oral food challenge. A positive (failed) challenge provides a
Idiopathic systemic capillary leak sound basis for continued avoidance of the food. A negative
syndrome (passed) challenge allows introduction or reintroduction of the
Excess endogenous histamine
specific food into the patient’s diet.111
Mastocytosis/clonal mast cell Unproved or disproved diagnostic methods, such as electro-
disorders" dermal skin testing and kinesiology, remain in use for assessment
Basophilic leukemia of patients with food allergy.115
In the future, in vitro tests that will distinguish reliably be-
Flush syndromes
tween sensitization without risk of clinical reactivity versus sen-
Perimenopause
Carcinoid
sitization with risk of clinical reactivity might be available.
Autonomic epilepsy These include measurement of allergen-specific basophil reac-
Medullary carcinoma thyroid tivity,116 assessment of sensitization by using recombinant
allergens,117 peptide microassay-based immunoassays to map
Adapted from references 24-26, 63-68, 109, and 110. IgE and IgG4 binding to sequential allergen epitopes,117-119 or
*Pollen-food allergy syndrome, also termed oral allergy syndrome, is elicited by a
variety of plant proteins, especially pathogen-related proteins that comprise a large
assessment of allergen-specific cytokine or chemokine
number of class 2 allergenic proteins found in various fruits and vegetables. These production.68
plant proteins cross-react with airborne allergens. Typical symptoms include pruritus, Assessment of medication- or biological agent–
tingling, and angioedema of the lips, tongue, palate, throat, and ears after eating raw, triggered anaphylaxis. Any medication or biological agent
but not cooked, fruits and vegetables. can potentially trigger anaphylaxis. For most agents, the antigenic
!This disease is due to histamine poisoning from fish, such as tuna, mackerel, saury,
mahi-mahi, anchovies, and herring, that are stored at increased temperatures (308C), at
determinants have not been characterized or validated; indeed, the
which bacteria such as Morganella marganii and Klebsiella pneumoniae produce relevant immunogenic prodrugs, haptens, metabolites, and un-
histamine and cis-urocanic acid. Symptoms occur from minutes to hours after identified degradation products or contaminants are often un-
ingestion of the fish and last for hours. They include flush (especially of the face and known.34,38,68 For most medications, with the exception of some
neck), angioedema, nausea, vomiting, diarrhea, and hypotension. An important clue to
the diagnosis is that more than 1 person eating the fish is usually affected. Skin prick
b-lactam antibiotics, appropriate reagents are not commercially
tests to fish are negative, and fish-specific IgE levels are absent or undetectable. available for use in skin tests, measurement of medication-spe-
"Anaphylaxis might be the first manifestation of mastocytosis or a clonal mast cell cific IgE levels, or other in vitro tests.34,68 Customized tests and
disorder. physician-monitored challenge/provocation tests performed in
jjNonorganic diseases also include Munchausen syndrome by proxy in a child or other specialized centers therefore play a central role in assessment
dependent, globus hystericus, and undifferentiated somatoform anaphylaxis.
of patients with a history of anaphylaxis triggered by a medica-
tion.34,68,120-122
For assessment of anaphylaxis triggered by vaccines to
prevent allergic diseases, skin prick tests should be performed
tests. Allergen-specific IgE levels with greater than 95% predic- not only with the immunizing agent but also with the relevant
tive risk values of a positive (failed) food challenge result have excipients in the culprit vaccine, such as gelatin in measles
been identified by using the ImmunoCAP (Phadia, Uppsala, vaccines or egg in some influenza vaccines and in yellow fever
Sweden). These levels are defined for cow’s milk (!15 kU/L), egg vaccine.48,68
(!7 kU/L), peanut (!14 kU/L), tree nuts (!15 kU/L), and fish Assessment of stinging insect–triggered anaphy-
(!20 kU/L); in infants lower values have been established for laxis. Standardized Hymenoptera venoms, such as honeybee,
milk (!5 kU/L) and egg (!2 kU/L).26 Predictive values for aller- yellow jacket, yellow hornet, white-faced hornet, and paper wasp,
gen-specific IgE levels potentially differ from one immunoassay are available for skin testing. Skin prick tests, if negative, should be
to another, and this can affect management decisions.26,68,113 followed by intradermal tests.52-54 Use of dialyzed venoms in skin
A positive skin test, an increased serum IgE level, or both to a tests is reported to improve the identification of venom-sensitized
specific food document sensitization to that food. Such tests are patients.123 For fire ant-triggered anaphylaxis, whole-body ex-
not diagnostic of anaphylaxis because sensitization to 1 or more tracts are used as skin test reagents.54,55 Measurements of
food allergens is common in the general population of healthy venom-specific IgE levels and fire ant whole-body extract–specific
J ALLERGY CLIN IMMUNOL SIMONS S169
VOLUME 125, NUMBER 2

TABLE VII. Laboratory tests: Acute anaphylactic episode

Histamine*
Obtain blood sample within 15 minutes to 1 hour of symptom onset* (use wide-bore needle, keep sample cold (at 4 degrees C), centrifuge it promptly, and
freeze plasma promptly).
Twenty-four-hour urine histamine and N-methylhistamine measurements might also be helpful.
Total tryptase* (pro, pro9, and mature forms of a/b-tryptases)
Obtain blood sample within 15 minutes to 3 hours of symptom onset.
Consider comparing the levels measured during the acute episode with a baseline level.!
If higher during the acute episode than in baseline serum, the diagnosis of anaphylaxis is confirmed."
If within normal limits during the acute episode, the diagnosis of anaphylaxis cannot be excluded.
Total tryptase level can be measured in postmortem serum.§
Additional laboratory testsjj
Adapted from references 24, 25, 68, 78, 79 and 81.
*Increases of histamine and tryptase levels are not specific for anaphylaxis. For example, histamine levels are increased in patients with scombroid poisoning and tryptase levels are
increased in patients with myocardial infarction, trauma, amniotic fluid embolus, and sudden infant death syndrome.
!Obtained 24 hours after resolution of the acute event or on stored serum, if available (levels are stable for !1 year if stored at -20 degrees C).
"If greater than 11.4 ng/mL in both acute and baseline sera, the diagnosis of mastocytosis or clonal mast cell disorder should be considered.
§Blood samples should be obtained from femoral vessels and not the heart; the level needs to be correlated with the clinical history because, as noted above, increased levels are
also found in other clinical situations, such as myocardial infarction, trauma, amniotic fluid embolism, and sudden infant death syndrome.
jjWhen sorting out the differential diagnosis of anaphylaxis, the detailed clinical history and physical examination might suggest the need for additional laboratory tests to confirm
or rule out diseases such as mastocytosis, basophilic leukemia, carcinoid (serum serotonin level and urinary 5 hydroxyindoleacetic acid), medullary carcinoma of the thyroid/
vasoactive polypeptide–secreting gastrointestinal tumor (substance P and vasointestinal polypeptide), pheochromocytoma (free metanephrine in plasma and urinary
vanillylmandelic acid), hereditary angioedema (C4 and C1 esterase inhibitor), or diagnostic imaging to confirm or rule out hydatid cysts. Investigation of the complement cascade
(C4a, C5a, and C3a), the contact system (bradykinin, high-molecular-weight kininogen, kallikrein–C1-inhibitor complexes, and factor XIIa–C1-inhibitor complexes), and
coagulation pathway (factors V, VIII, and fibrinogen), although usually not performed, might support the clinical diagnosis of anaphylaxis; however, these tests also appear to lack
specificity.

TABLE VIII. Confirmation of a potential trigger for an anaphylactic episode

Allergen skin tests
Percutaneous (prick or puncture)*
Intradermal (intracutaneous) for selected allergens such as insect venoms and b-lactam antibiotics!
Allergen-specific serum IgE levels
Quantitative ELISAs"
Allergen challenge tests§
Most commonly performed with foods or medications
Other challenge tests
Exercisejj
Cold
Heat
Sunlight
Work up of patients with idiopathic anaphylaxis (in whom detailed history of antecedent events/exposures does not yield any clues about triggers and skin test
results and allergen-specific IgE measurements are negative)
Search for a previously unrecognized trigger
Measure serum baseline total tryptase levels (normal value, <11.4 ng/mL)
Inspect skin closely for evidence of urticaria pigmentosa
Consider bone marrow biopsy (perform c-Kit mutational analysis in addition to usual stains for identification of spindle-shaped mast cells in clusters)

Adapted from references 24-26, 34, 52, 58, 61, 67, 100-102, and 111.
*Allergens for skin testing should be selected on the basis of the history. Standardized extracts are available only for some Hymenoptera venoms and some inhalant allergens.
Patients should discontinue H1-antihistamines 7 days before skin testing. Many people in the general population are sensitized to allergens (eg, 60% of teens to food and as many as
28.5% of adults to venom).
!Intradermal tests are generally contraindicated in food allergy because of the high likelihood of false-positive results and the possibility of triggering anaphylaxis.
"Available commercially for foods, insect venoms, and latex but not for most medications or biological agents. Refer to predictive values, where available, for foods such as peanut,
tree nuts, fish, milk, and egg.
§Open, single-blind, or double-blind depending on clinical history and allergen. ‘‘First do no harm’’: challenge only if assessment (clinical history, skin tests, and/or measurement
of allergen-specific IgE levels) indicate that the patient is at low risk for anaphylaxis. Perform only under medical supervision in a hospital or other health care facility.
jjAssessment of cotriggers, such as a food, medication, or cold exposure, is needed.

IgE levels are commercially available. Some patients with a history
of Hymenoptera sting–triggered anaphylaxis have negative skin
test responses to insect venoms but increased specific IgE levels
to venoms and vice versa.52,124 Challenge/provocation tests with
stinging and biting insects are potentially dangerous and are
used only in research.52-57,68,125
Positive intradermal tests to stinging insect venoms, increased
venom-specific IgE levels, or both occur in up to 28.5% of the general
adult population, most of whom do not have systemic symptoms
after an insect sting.52-54,68 It is therefore critically important that the
test results be interpreted in the context of the clinical history. Cross-
reacting carbohydrate derivatives between venom allergens and plant
S170 SIMONS
or other nonvenom allergens might account for many of these posi-
tive test results. In some centers additional tests used to assist in in-
terpretation of positive test results include consideration of total
IgE levels as well as venom-specific IgE levels,125 and measurement
of basophil activation markers, such as CD63 or CD203c after incu-
bation with different concentrations of venom.53,68,125
Conversely, venom skin tests might be negative and venom-
specific IgE levels might be absent or undetectable in patients with a
convincing history of insect sting–triggered anaphylaxis. Negative
tests might be due to rare IgE- or non–IgE-mediated reactions to a
protein or peptide constituent127 such as melittin in honeybee venom
or mastoparan in vespid venom; variability of intradermal testing;
anergy in patients tested within a few weeks of the sting; decrease
in the immune response to venom over time in patients stung
many years before testing; or increased patient vulnerability to ana-
phylaxis. As noted previously, risk of severe or fatal anaphylaxis in-
creases with older age; concurrent diseases, including CVDs; and
concurrent use of medications, such as b-blockers or angiotensin-
converting enzyme inhibitors,52,53,97,103 as well as in patients with
mastocytosis, clonal mast cell disorders, or increased baseline tryp-
tase levels.52,53,72,100-103 If the baseline total tryptase level is greater
than 11.4 ng/mL (the new upper limit of normal), meticulous exam-
ination for cutaneous mastocytosis is indicated, and if the level is
greater than 20 ng/mL, a bone marrow biopsy is indicated, even if
cutaneous manifestations are absent.67 Also, in some patients clin-
ical risk of anaphylaxis is increased by factors such as a recent sting;
a previous severe systemic reaction to a sting; a sting on the head,
neck, or throat; or the entomology of the stinging insect.52-54,68,103
Assessment of anaphylaxis from other triggers. For
assessment of anaphylaxis triggered by natural rubber latex, skin
prick tests should be performed with commercial latex allergens,
where available, or with extracts of rubber products, such as natural
rubber latex gloves, where commercial allergens are not available.
Consideration should be given to testing with foods that cross-react
with latex, such as banana, kiwi, papaya, avocado, potato, and
tomato.58,68 Latex-specific IgE antibodies can also be measured.
For assessment of exercise-triggered anaphylaxis, skin tests
should be performed with potential food allergen cotriggers.61 An
exercise intensity threshold can be defined in an exercise challenge
test to diagnose food-dependent exercise-induced anaphylaxis.128
Assessment of idiopathic anaphylaxis. When a metic-
ulous history of antecedent exposures and events does not yield
any clues about potential triggers and when allergen skin tests are
negative and specific IgE measurements are absent or undetect-
able to selected common allergens, patients are said to have
idiopathic anaphylaxis. Before making this diagnosis, physicians
should consider the possibility of a hidden or previously unrec-
ognized trigger. Sensitization to a novel trigger for which there is
no commercially available test allergen can be identified through
a history of the event and confirmed by objective tests. These
potentially include skin testing the patient and 1 or more controls
with crude extracts of the suspected culprit allergen (although
there is no quality assurance that such extracts contain the
relevant allergenic components) and/or development of custom-
ized, sensitive, specific ELISAs and other in vitro tests, including
gel electrophoresis and IgE immunoblotting, for identification of
specific IgE to the suspect allergen.63,68,69
The serum total tryptase level should be measured in all
patients with idiopathic anaphylaxis.63-68,78,100-103 This important
screening test for mastocytosis reflects the increased burden of
mast cells in all forms of this disease.78
J ALLERGY CLIN IMMUNOL
FEBRUARY 2010
MANAGEMENT OF PATIENTS AT RISK FOR
ANAPHYLAXIS IN COMMUNITY SETTINGS
Long-term preventive measures include optimal management
of relevant comorbidities, such as asthma, other chronic respira-
tory diseases, CVDs, and mastocytosis and clonal mast cell
disorders.63-67,97-102 These measures also include discussion of
the relative benefits and risks of concurrent medications (eg,
b-blockers, angiotensin-converting enzyme inhibitors, and others
that are widely and effectively used in the management of CVDs)
with the patient and his or her cardiologist and documentation of
the rationale for treatment decisions in the patient’s medical
record.97-99,103
With the exception of venom immunotherapy for patients with
insect sting–triggered anaphylaxis, current recommendations for
prevention of anaphylaxis and emergency preparedness for
treatment of anaphylaxis in the community are based on expert
opinion and consensus rather than on randomized, double-blind,
placebo-controlled trials. Preventive strategies for anaphylaxis in
community settings that involve trigger avoidance and immuno-
modulation are summarized in Table IX.1,2,24-
26,34,52,54,58,69,93,129-153
Follow-up at regular intervals is an impor-
tant aspect of long-term risk reduction.
Long-term risk reduction: Prevention of anaphylaxis
Anaphylaxis triggered by food. Written personalized
information about avoidance of confirmed relevant food triggers,
including lists of common hidden sources of the food or foods and
high-risk situations, such as buffet and catered meals and
unlabeled desserts, baked goods, and candies, should be provided.
Patients should be directed to resources that provide up-to-date,
consistent information about avoidance of the specific food or
foods (Table IX).26,129 Food avoidance measures potentially de-
crease quality of life for those at risk of anaphylaxis and for their
caregivers130,131 because of lifestyle changes that disrupt
activities, uncertainty about ambiguities in advisory labeling,132
and anxiety about the risk of accidental exposures.26,133 Strict
avoidance of many foods potentially leads to nutritional
deficiencies.26 Some patients at risk for anaphylaxis to foods, or
their caregivers, turn to complementary and alternative medicine
for relief.115
Allergen-specific oral immunotherapy is currently a research
procedure for prevention of anaphylaxis triggered by food.
Clinical trials with foods such as milk, egg, or peanut have been
conducted in carefully selected patients in appropriately equipped
food allergy research centers by physicians and other health care
professionals who have experience in performing food chal-
lenges, administering oral immunotherapy, and diagnosing and
treating anaphylaxis.108,112,134-141 A few of the studies have had a
double-blind, placebo-controlled design.137 Adverse effects have
been common with some oral immunotherapy dosing regimens,
especially on the initial dose escalation day and on subsequent
dose build-up days.141
In some of these studies, clinical desensitization to a food has
been accompanied by long-term, food-specific humoral and
cellular changes,138,140 including decreased titrated skin prick
tests, decreased basophil activation, decreased IgE levels, and in-
creased IgG4, IL-10, IFN-g, and TNF-a levels.140 Studies in pro-
gress will resolve the issue as to whether oral immunotherapy for
food-triggered anaphylaxis leads not only to clinical desensitiza-
tion but also to true immunologic tolerance in which patients
J ALLERGY CLIN IMMUNOL SIMONS S171
VOLUME 125, NUMBER 2

TABLE IX. Preventive strategies for anaphylaxis in community settings

Allergen-specific trigger avoidance based on history of exposure and confirmation of sensitization (strength of recommendation 5 C)
Foods,* including additives and contaminants
Medications and biological agents!
Insect stings and bites
Natural rubber latex*
Inhalants
Seminal fluid
Occupational allergens
Other
Nonimmunologic triggers: avoid relevant exposure (strength of recommendation 5 C)
Exercise-induced anaphylaxis"
Cold air or water
Heat
Sunlight/UV radiation
Medications, such as opioids
Ethanol
Immunomodulation
Food: Currently, oral immunotherapy is a research procedure supervised by physicians in specialized food allergy centers (strength of recommendation
pending).
Insect venoms: allergen-specific immunotherapy (strength of recommendation 5 A)
Medications!: desensitization (strength of recommendation 5 B)
Seminal fluid: desensitization (strength of recommendation 5 C)
Idiopathic anaphylaxis (for frequent episodes only; strength of recommendation 5 C)
Oral glucocorticoid, such as prednisone; H1-antihistamine, such as cetirizine (used for prophylaxis)

Adapted from reference 153 and others; see text for details.
*These Web sites consistently provide accurate up-to-date information: the Food Allergy and Anaphylaxis Network (www.foodallergy.org); the American Latex Allergy
Association (www.latexallergyresources.org); the American Academy of Allergy, Asthma & Immunology (www.aaaai.org); and the American College of Allergy, Asthma &
Immunology (www.acaai.org).
!Avoid the medications suspected of triggering anaphylaxis and substitute a non–cross-reacting medication, preferably from a different therapeutic class. If this is not possible,
desensitization should be performed (eg, for b-lactam antibiotics, NSAIDs, and chemotherapy drugs).
"Avoid relevant cotriggers, such as food, medication, cold air, or cold water.

remain desensitized even if the food is not eaten on a regular
basis.112,134,135
Future directions in specific immunotherapy to food and other
allergens that trigger anaphylaxis might include allergen admin-
istration through the sublingual route, ‘‘engineered’’ recombinant
protein allergens, a mixture of major recombinant allergens,
CpG-oligonucleotide–conjugated allergens, peptides or polymers
of major allergens, and other novel approaches.112
Immunomodulatory approaches that are not specific for a
particular food allergen are also being studied. Food Allergy
Herbal Formula-2, a well-characterized mixture of Chinese herbs
that prevents food-induced anaphylaxis and leads to long-lasting
immunologic tolerance in a murine model, has now entered
clinical trials.142 Subcutaneous injections of anti-IgE antibody
potentially provide an increased margin of protection against
food and other allergen triggers of anaphylaxis for many, although
not all, patients at risk (Table IX).143
Medication- or biological agent–triggered anaphy-
laxis. For anaphylaxis triggered by a medication or a biological
agent, avoidance is critically important. An alternative non–cross-
reacting agent, preferably from a different therapeutic class but
sometimes from the same class, can often be substituted effec-
tively and safely.34 Where this is not possible, desensitization
with the offending agent is indicated.34,144 Standardized 12-step
desensitization protocols in which antigens are introduced in an
incremental manner over several hours have been published for
some agents, such as b-lactam antibiotics or other antibiotics, as-
pirin or other NSAIDs, insulin, and chemotherapeutic agents, in-
cluding taxanes and platins, as well as mAbs.144 Once achieved,
desensitization is maintained through regular administration of
the medication. Immunologic tolerance does not occur, and if
the medication is discontinued, symptoms can recur when it is re-
started.144 Desensitization should be conducted in an appropri-
ately equipped health care facility staffed by health care
professionals who are trained and experienced in using desensi-
tization protocols and in the recognition and treatment of break-
through symptoms, including those of anaphylaxis.34,144 The
cellular and molecular mechanisms underlying temporary desen-
sitization without immunologic tolerance are not yet fully
understood.144
In patients with a history of vaccine- or vaccine component–
triggered anaphylaxis who have negative skin tests to the vaccine
and its components, it is highly unlikely that IgE antibody is
present. The vaccine can therefore be administered in the usual
manner; however, it is prudent to observe such patients for
1 hour afterward instead of the customary 30 minutes. In patients
with a positive history and positive skin tests, a suitable
alternative vaccine is sometimes available; for example, egg-
free seasonal influenza vaccine and egg-free pandemic A/H1N1
vaccine grown in mammalian cell culture systems are now
available in some countries. If a suitable alternative vaccine is
not available, the culprit vaccine should be administered in an
appropriately equipped and staffed health care facility by using a
graded-dose protocol (Table IX).48
Stinging insect–triggered anaphylaxis. For anaphylaxis
triggered by stinging insects, avoidance of exposure involves
several approaches. Yellow jacket, hornet, or wasp nests or fire ant
mounds in the vicinity of the patient’s home should be profession-
ally exterminated. Awareness of high-risk outdoor work or leisure
activities, such as gardening, camping, picnicking, or barbecuing,
S172 SIMONS
is important. When outdoors, appropriate protective clothing,
including shoes and socks, should be worn. Personal insect
repellents, such as DEET, are not effective in preventing insect
stings in contrast to their efficacy in preventing insect bites.54
In most patients with Hymenoptera venom–triggered anaphy-
laxis, a 3- to 5-year course of subcutaneous injections of the
relevant standardized insect venom or venoms significantly
reduces the risk of anaphylaxis from a subsequent sting and
provides long-lasting protection.52-54,124 This potentially curative
treatment is underused.53 In children a 98% protection rate can be
achieved, and the effect lasts for decades after venom injections
are discontinued.52,145 Use of purified extracts potentially reduces
large local reactions during venom immunotherapy.146 Venom
immunotherapy can be safely administered to all those at risk, in-
cluding high-risk patients with mastocytosis or clonal mast cell
disorders, although a slow rate of dose escalation is often neces-
sary in such patients.147,148 Anti-IgE antibody is reported to be
useful in controlling reactions to venom immunotherapy in pa-
tients with mastocytosis.149 For prevention of anaphylaxis from
fire ant stings54,55 or from insect bites,54,57 subcutaneous injec-
tions of the relevant whole-body extracts are used.
In adults venom immunotherapy significantly reduces sting-
induced cutaneous systemic reactions and is therefore indicated
for patients with sting-induced generalized urticaria and no other
systemic symptoms.52,124 It also reduces large local reactions to
stings and might be considered for at-risk patients who cannot to-
tally avoid insect exposure, such as beekeepers, and/or those who
experience frequent or severe large local reactions.150 In children,
venom immunotherapy is not indicated either for sting-induced
generalized urticaria without other systemic symptoms or for
large local reactions (Table IX).145
Anaphylaxis induced by other triggers. Avoidance of
the relevant specific confirmed trigger is the key to prevention of
anaphylaxis recurrence, such as avoidance of natural rubber
latex58 or occupational allergens.1,2,24,25,69 Desensitization pro-
vides short-term immunomodulation for patients at risk of
anaphylaxis to seminal fluid.59 In the future, regular subcutaneous
injections of anti-IgE antibody might be indicated for patients
with anaphylaxis triggered by various allergen triggers. For ana-
phylaxis induced by some nonimmune triggers, such as cold, heat,
sunlight/UV radiation, or ethanol, avoidance of the trigger is the
key to prevention of recurrences (Table IX).25
Exercise-triggered anaphylaxis. Strategies for prevention
of exercise-induced anaphylaxis include strict avoidance of
relevant cotriggers, such as food, medication, or ethanol inges-
tion and cold air or cold water exposure, and awareness of other
potential concomitant risk factors, such as acute infection,
emotional stress, menses (premenstrual and ovulatory phases),
extremes of temperature and humidity, and high pollen counts.
Additional precautions include never exercising alone, discon-
tinuing exertion immediately when the first symptom of ana-
phylaxis is noted, always carrying 1 or more epinephrine
autoinjectors, and carrying a cell (mobile) phone for calling
911/emergency medical services during activities such as long-
distance running or cross-country skiing. Premedication and
warm-up are not effective in preventing exercise-induced
anaphylaxis (Table IX).24,25,61
Idiopathic anaphylaxis. Immunomodulation with pharma-
cologic agents is often recommended for patients with frequent
episodes of idiopathic anaphylaxis, which is defined as more than
6 per year or more than 2 per 2 months. One example of a
J ALLERGY CLIN IMMUNOL
FEBRUARY 2010
prophylaxis regimen involves 60 to 100 mg of prednisone each
morning for 1 week, followed by 60 mg on alternate mornings for
3 weeks and then gradual tapering of the dose over 2 months, in
addition to an H1-antihistamine, such as 10 mg of cetirizine
daily.63 Anti-IgE antibody injections have been reported to be
helpful in patients with idiopathic anaphylaxis and in anaphylaxis
with no apparent trigger that occurs in patients with mastocytosis.
(Table IX)151,152
Long-term risk reduction: Emergency preparedness
for anaphylaxis recurrences in the community
Those at risk for anaphylaxis in the community and their
caregivers should be prepared to recognize episodes that occur
despite best efforts to avoid the relevant trigger and other
preventive measures and to provide prompt life-saving first-aid
treatment of such episodes.2,24-26,34,52,54,69,93,153 Emergency pre-
paredness involves carrying 1 or more epinephrine autoinjectors,
having an anaphylaxis emergency action plan, and wearing
appropriate medical identification.1,2,24-26,54,69,153
Epinephrine (adrenaline): the medication of choice.
For treatment of an anaphylaxis recurrence in the community,
injection of epinephrine is the first-aid medication of choice, as
recommended in all anaphylaxis guidelines. The rationale for this
is summarized in Table X.24,154,156-162 Most guidelines recom-
mend injecting epinephrine from an autoinjector intramuscularly
in the midanterolateral aspect of the thigh. The first aid dose of ep-
inephrine is 0.01 mg/kg of a 1 mg/mL (1:1,000) dilution to a max-
imum dose of 0.5 mg in an adult or 0.3 mg in a child. This dose can
be repeated every 5 to 15 minutes, as needed.154,155,163-165 Pa-
tients should not suddenly sit or stand after receiving an epineph-
rine injection because this can lead to the empty inferior vena
cava/empty ventricle syndrome and sudden death.166
In patients with anaphylaxis, epinephrine has potent life-saving
a1-adrenergic vasoconstrictor effects on the small arterioles and
precapillary sphincters in most body organ systems.156 It de-
creases mucosal edema, thereby preventing and relieving upper
airway obstruction, and it also prevents and relieves hypotension
and shock (Table X).156-160 In addition, its b1-adrenergic effects
lead to increased force and rate of cardiac contractions, and its
b2 effects lead to increased bronchodilation and decreased release
of mediators, such as histamine and tryptase, from mast cells and
basophils.156
Prompt injection is important. In most countries the highest
epinephrine dose currently available in an autoinjector is 0.3 mg.
This dose is low compared with the initial adult dose of 1 mg
epinephrine used in cardiopulmonary resuscitation and is unlikely
to be effective if anaphylaxis has progressed to the point at which
cardiopulmonary resuscitation is needed. Delayed injection of
epinephrine is associated with fatal anaphylaxis18-21 and also con-
tributes to the increased likelihood of biphasic anaphylaxis, which
is defined as symptom recurrence 1 to 72 hours (usually within 8
hours) after resolution of the initial symptoms despite no further
exposure to the trigger.167-169
The best way of providing first-aid treatment with epinephrine
(adrenaline) for anaphylaxis in the community is by using an
autoinjector; however, currently available autoinjectors have a
number of limitations. Only 2 fixed epinephrine doses, 0.15 mg
and 0.3 mg, are available in autoinjector formulations in most
countries (EpiPen, Dey, LP, Napa, Calif; Twinject, Shionogi &
Co, Ltd, Osaka, Japan; Anapen, Lincoln Medical, Salisbury,
Wiltshire, United Kingdom). The 0.15 mg dose is too high for
J ALLERGY CLIN IMMUNOL
VOLUME 125, NUMBER 2
TABLE X. Epinephrine (adrenaline): Medication of first choice for anaphylaxis
Strength of recommendation
Pharmacologic effects when given by injection (oral administration is
ineffective because of rapid metabolism in the GI tract)
Practical aspects
Potential adverse effects (after usual dose of 0.01 mg/kg to a maximum of
0.5 mg [adults] IM)*
Potential adverse effects (after overdose, such as IV bolus dose, overly
rapid IV infusion, or erroneous administration of a concentrated
epinephrine solution 1:1,000 [1 mg/mL] by the IV route)!
Comment: why the intramuscular route is preferred
Adapted from references 24 and 154-162.
GI, Gastrointestinal; IM, intramuscular; IV, intravenous.
*The epinephrine dose recommended for initial treatment of anaphylaxis is lower than the dose recommended for initial use in cardiopulmonary resuscitation and is unlikely to be
effective after cardiac arrest has occurred. Ideally, epinephrine doses should be stated concentrations (ie, milligrams per milliliter) rather than as ratios; however, both methods are
in common use.
!Intravenous infusion of epinephrine presents a high risk of harmful side effects. It should be given only by physicians who are trained and experienced in the dose titration of
vasopressors (preferably by using an infusion pump) against continuous hemodynamic monitoring.
"Epinephrine enhances blood flow in coronary arteries because of increased myocardial contractility and increased duration of diastole. This action and the vasodilator effect in
skeletal muscle produced by endogenous epinephrine are well-recognized aspects of the fight-or-flight response.
infants and children weighing less than 15 kg. The 0.3 mg dose is
too low for children weighing more than 30 kg and for teens and
adults. In the United Kingdom a 0.5 mg epinephrine dose is
available in the Anapen. Autoinjectors with 1.43 cm needles
might not achieve intramuscular injection in some children and
adults, as ascertained by using computed tomographic scans of
the thigh to measure the distance from the skin to the surface of
the vastus lateralis muscle.170,171 The force of the injection likely
also contributes to intramuscular deposition and rapid absorption
of epinephrine.172
Health care professionals need to be trained to use epinephrine
autoinjectors correctly and safely in order to train and coach those
at risk for anaphylaxis and their caregivers in how to use them
correctly and safely.173 Unintentional injections from epinephrine
autoinjectors into fingers, thumbs, and hands by patients self-in-
jecting or by caregivers injecting children or others have been re-
ported to poison control centers with increasing frequency in the
past decade. These unintentional injections might not only result
in injury but also in partial or complete loss of the epinephrine
dose for the person having an anaphylactic episode, the so-called
‘‘lost dose hazard.’’174,175 Epinephrine autoinjectors with
SIMONS S173
B-C
At a1-receptor
[ Vasoconstriction/[ vascular resistance in most body organ systems
[ Blood pressure
Y Mucosal edema (larynx)
At b1-receptor
[ Heart rate
[ Cardiac contraction force
At b2-receptor
Y Mediator release
[ Bronchodilation
[ Vasodilation
Y Mucosal edema and relieves upper airway obstruction
Y Wheezing
Y Hives
[ Blood pressure and prevents and relieves hypotension and shock
Anxiety, pallor, tremor, palpitations, dizziness, and headache; these
symptoms indicate that an appropriate pharmacologic dose has been
injected.
Pulmonary edema, hypertension, angina, myocardial infarction, ventricular
arrhythmias; note that the latter 3 adverse effects also potentially occur
in untreated anaphylaxis when subclinical coronary artery disease is
unmasked, because the heart itself is a potential target organ in
anaphylaxis."
Epinephrine has a vasodilator effect in skeletal muscle."
Skeletal muscle is well vascularized.
After intramuscular injection into the vastus lateralis, absorption is rapid,
and epinephrine reaches the central circulation rapidly.
Rapid absorption is critical in anaphylaxis in which the median time to
respiratory or cardiac arrest is 15 minutes (venom) to 30 minutes (food).
improved design, including needle protection features, are being
introduced.
Up to 20% of patients who receive an initial first-aid dose of
epinephrine for treatment of anaphylaxis in the community are
reported to require a second dose, either because of ongoing
symptoms or because of biphasic anaphylaxis.167-169,176-178 Most
patients with anaphylaxis respond promptly to epinephrine injec-
tions; the potential reasons for apparent lack of response in a minor-
ity of patients are summarized in Table XI.158,166,170,171,175,178-181
Transient pharmacologic effects of epinephrine, such as pallor,
tremor, anxiety, palpitations, headache, and dizziness, that occur
within 5 to 10 minutes after injection are usually mild and confirm
that a therapeutic epinephrine dose has been given. Serious adverse
effects, such as pulmonary edema or hypertension, are usually
attributable to epinephrine overdose. Although they can occur after
administration by any route, they are most commonly reported after
either an intravenous bolus dose, an overly rapid intravenous
infusion, or an intravenous injection of a concentrated 1 mg/mL
(1:1,000) epinephrine solution instead of the dilute 0.1 mg/mL
(1:10,000) epinephrine solution appropriate for intravenous
infusion.24,154
S174 SIMONS J ALLERGY CLIN IMMUNOL
FEBRUARY 2010

TABLE XI. Reasons for apparent lack of response to epinephrine

Physician-related factors
Error in diagnosis*
Empty ventricle syndrome!
Patient-related factors
Rapid anaphylaxis progression
Patient taking a medication that interferes with optimal epinephrine effect, such as an a-adrenergic blocker or b-adrenergic blocker
Epinephrine-related factors
Epinephrine autoinjector not available"
Epinephrine autoinjector not prescribed by physician
Epinephrine autoinjector not affordable (prescription not picked up)
Injected too late
Dose too low on a milligram per kilogram basis
Dose too low because of injection of epinephrine that is past the expiry date§
Injected using incorrect technique, such as not enough force
Injection route not optimaljj
Injection site not optimal
Adverse reaction to sodium metabisulfite preservative in the epinephrine solution (rare)

Adapted from references 158, 166, 170, 171, 175, and 178-181.
*For example, if epinephrine is injected for a disease, such as nonallergic angioedema or food protein–induced enterocolitis, that would not be expected to respond well to it.
!Occurs when the epinephrine injected cannot circulate in the body because the patient is suddenly placed upright and the vena cava (and ventricle) empties.
"In many countries life-saving epinephrine autoinjectors are not available for those at risk of anaphylaxis. Existing alternatives cannot be depended on to produce high tissue
concentrations of epinephrine rapidly. These include having a patient or caregiver draw up epinephrine from an ampule, use of a syringe prefilled with epinephrine, or use of an
epinephrine metered-dose inhaler.
§The maximum shelf-life of EpiPen and Twinject autoinjectors is 12 to 18 months. The maximum shelf life of AnaPen autoinjectors (available in the United Kingdom) is 18 to 24
months. The maximum shelf life of a syringe prefilled with epinephrine in a physician’s office is 3 to 4 months. In vitro degradation (breakdown) products of epinephrine are
ineffective in patients with anaphylaxis.
jjEpinephrine through other routes, such as subcutaneous injection or inhalation from a metered-dose inhaler or nebulizer and compressor is not recommended for the treatment of
anaphylaxis because it is more difficult to achieve high plasma and tissue concentrations rapidly when these routes are used.

Traditionally, many physicians have been reluctant to inject
epinephrine in middle-aged or older patients with anaphylaxis
because of concerns regarding cardiac adverse effects. In fact, the
heart is a potential target organ in anaphylaxis. In healthy people
mast cells are present throughout the myocardium (between
myocardial fibers, around blood vessels, and in the coronary
artery intima).72,97 In patients with coronary artery disease, the
number and density of cardiac mast cells is increased because
mast cells are also present in atherosclerotic plaques, where
they contribute to atherogenesis.97 Histamine, leukotrienes, plate-
let-activating factor, and other mediators released after mast cell
stimulation potentially lead to coronary artery spasm.97 Patients
with anaphylaxis can present with acute coronary syndrome sec-
ondary to either vasospasm or acute plaque rupture and thrombus
formation. In patients with coronary artery disease, the use of ep-
inephrine requires caution; however, concerns about its potential
adverse effects need to be weighed against the cardiac risks of un-
treated anaphylaxis and the knowledge that epinephrine injection
usually enhances blood flow in the coronary arteries because its
b2-adrenergic action leads to increased myocardial contractility
and increased duration of diastole compared with systole
(Table X).24,25,97,161,162
Other medications. More than 40 H1-antihistamines are
available for use,182 and many of these medications are recommen-
ded for use in anaphylaxis; in some anaphylaxis guidelines, dosage
regimens are provided for up to 7 different H1-antihistamines. H1-
antihistamines do not prevent or relieve upper or lower airway ob-
struction, hypotension or shock.182,183 After oral administration,
their onset of action ranges from 1 to 3 hours.182 The rapid improve-
ment in symptoms sometimes attributed to oral H1-antihistamines
likely reflects spontaneous resolution of the anaphylactic episode.
First-generation, potentially sedating H1-antihistamines, such as
diphenhydramine, chlorpheniramine, and promethazine, have a
poor benefit/risk ratio.182,184 When self-administered in patients
with anaphylaxis, these medications potentially impair self-recog-
nition of symptoms. When given to a child, they potentially compli-
cate interpretation of CNS symptoms and signs, such as drowsiness.
An H1-antihistamine might be useful as an adjunctive measure to
relieve residual hives that have not disappeared after epinephrine in-
jection (Table XII).153,183
b2-Adrenergic agonists do not have a vasoconstrictor effect and
do not decrease mucosal edema, prevent or relieve upper airway
obstruction, hypotension or shock. They are potentially useful
when administered by nebulization as an adjunctive measure to
relieve residual bronchospasm that has not disappeared after epi-
nephrine injection (Table XII).154
Glucocorticoids are traditionally given to prevent and relieve
biphasic or protracted anaphylaxis (Table XII).185
Emergency preparedness in the community: Addi-
tional measures. Almost 40% of persons at risk of anaphy-
laxis in the community reportedly use a written anaphylaxis
emergency action plan.178 Most plans list common symptoms
and signs of anaphylaxis and emphasize the importance of using
the epinephrine autoinjector promptly and of calling 911 or
emergency medical services promptly (download from
www.aaaai.org).69,186 Plans should be personalized for each
at-risk patient by listing comorbidities and concurrent medica-
tions, describing the epinephrine autoinjector and dose pre-
scribed for the patient, and providing appropriate contact
telephone numbers, such as those of family members.69,186 Plans
need to be updated and discussed with the patient, and if rele-
vant, his or her caregivers, on a regular basis. Formal evaluation
of the clinical efficacy and cost-effectiveness of these plans is
needed.187
J ALLERGY CLIN IMMUNOL SIMONS S175
VOLUME 125, NUMBER 2

TABLE XII. Adjunctive medications for the treatment of anaphylaxis

Glucocorticoids* (oral,
H1-antihistamines* (oral, such such as prednisone;
as cetirizine; H2-antihistamines* b2-Adrenergic agonists* IV, such as
Medication (example) IV, such as diphenhydramine) (ranitidine) (salbutamol [albuterol]) methylprednisolone)

Strength of C C
recommendation*
Pharmacologic effects At H1-receptor At H2-receptor
Y Gastric acid secretion
Y Itch (skin, mucus membranes) Y Vascular permeability
Y Flush Y Hypotension
Y Hives Y Flushing
Y Sneezing Y Headache
Y Rhinorrhea Y Tachycardia
Y Chronotropic and
inotropic activity
Y Mucus production
(airway)
Practical aspects Y Itch and hives but not life- Small additive effect
saving in anaphylaxis (10% or so) when used
in conjunction with an
H1-antihistamine for
Y in vascular
permeability,
Y flushing, and
Y hypotension
Potential adverse effects First-generation drugs cause Ranitidine: unlikely
(usual doses) sedation and impair cognitive cimetidine: potentially
function. causes hypotension if
infused rapidly
Potential adverse effects Coma, respiratory depression Unlikely
(overdose)
Comment Many different H1-antihistamines Not mentioned in most
and different dose regimens are anaphylaxis guidelines;
listed as adjunctive an H2-antihistamine
medications in anaphylaxis should not be used
guidelines. alone in anaphylaxis; if
used, it should be given
with an H1-
antihistamine.
C C
At b2-receptor
[ Bronchodilation
Y Wheeze, cough, and
shortness of breath but
do not Y upper airway
obstruction or relieve
hypotension and are not
life-saving in
anaphylaxis
Tremor, tachycardia,
dizziness, jitteriness
Headache, hypokalemia
Deliver by nebulization
and face mask.
Y Late-phase allergic
response to allergen
Effects take several hours;
used to prevent
biphasic or protracted
anaphylaxis; however,
there is no evidence
from high-quality
randomized controlled
trials that this occurs.
Unlikely to occur during a
short 1- to 3-day course
Unlikely
Different glucocorticoids
and different dose
regimens are used;
these medications are
unlikely to play a role
in the initial minutes to
hours of an
anaphylactic episode.

There are no randomized double-blind, placebo-controlled trials of any of these medications in the treatment of acute anaphylaxis episodes. The route of administration of
H1-antihistamines and glucocorticoids depends on the severity of the anaphylaxis episode. Adapted from reference 153.
*For use in anaphylaxis.

Those at risk for anaphylaxis in the community should wear
medical identification jewelry that provides worldwide access to a
patient registry service 24 hours a day, 365 days of the year, so that
health care professionals treating them can obtain relevant
information about their triggers, concomitant diseases, and con-
current medications if needed. An anaphylaxis wallet card listing
relevant confirmed triggers, concomitant diseases, and concurrent
medications is available at www.aaaai.org.69,153
An approach to anaphylaxis education for health care profes-
sionals, people at risk of anaphylaxis and their caregivers, and the
general public is outlined in Table XIII.69,153,188,189 The consis-
tent message in anaphylaxis education should be that anaphylaxis
is potentially a killer allergy, not a trivial lifestyle disease, and that
prompt treatment is life-saving.69,153
Anaphylaxis education projects are now becoming a priority in
some communities. The main goal of these efforts is to teach
people to act promptly, recognize anaphylaxis, use an epinephrine
autoinjector correctly and safely, call for help, transfer the patient
to a health care facility, and also to recommend follow-up,
preferably with an allergy/immunology specialist. Examples of
specific education projects are those focusing on anaphylaxis
after omalizumab injection in a physician’s office,190 and on fol-
low-up of patients with anaphylaxis who are treated in the emer-
gency department.191 Many patients discharged from an
emergency department after anaphylaxis treatment still do not re-
ceive a prescription for self-injectable epinephrine or a referral to
a specialist physician.192 Lack of access to epinephrine autoinjec-
tors for children experiencing anaphylaxis in schools remains a
concern.188,189,193,194
EMERGENCY MANAGEMENT OF ACUTE
ANAPHYLAXIS IN A HEALTH CARE FACILITY
Emergency management of anaphylaxis in a health care facility
is reviewed in depth elsewhere.154,155,163,164 In any physician’s
S176 SIMONS J ALLERGY CLIN IMMUNOL
FEBRUARY 2010

TABLE XIII. Anaphylaxis education

Health care professionals
Who: physicians, nurses, pharmacists, emergency medical technicians, and first responders
What: definition of anaphylaxis (new); shock not necessarily a criterion for diagnosis
Common triggers
Emergency preparedness
Recognition of evolving symptoms and signs; can be difficult in those unable to describe their symptoms, such as infants, or patients with
dysphonia, dyspnea, or shock; severity varies among patients and in the same patient from one episode to another
Treatment: promptly and simultaneously inject epinephrine, activate 911 or emergency medical services,* and place patient on the back or in position of
comfort with lower extremities elevated
When: at regular intervals
Key messages: Anaphylaxis can kill rapidly (within 15 minutes after an insect sting and within 30 minutes after ingestion of a food trigger). Inject first-aid
dose of epinephrine promptly. Especially, do not hesitate if the patient has trouble breathing, throat tightness, or altered level of consciousness.
People at risk for anaphylaxis
Who: those who have experienced anaphylaxis previously and are at risk for recurrences and their families; for teens and young adults, their peers
What: triggers of anaphylaxis, prevention of episodes (trigger specific), emergency preparedness—recognize symptoms and signs, inject epinephrine;
activate emergency medical services,* notify family
Hands-on epinephrine autoinjector training and coaching
When: teachable moments in the weeks or months after an anaphylactic episode and then at yearly intervals or more often
Key messages: Death from anaphylaxis can occur within minutes. Promptly inject epinephrine, activate emergency medical services*
Place the patient on the back or in a position of comfort with lower extremities elevated.
General public
Who: educators, coaches, camp directors, child care providers, food industry workers, restaurant workers, and transportation workers
What: Anaphylaxis occurs in infants, children, teens, and adults who appear to be in excellent health until exposed to their trigger. Symptoms that mandate
immediate treatment are sudden difficulty breathing, throat tightness, and altered level of consciousness.
When: at regular intervals, such as the start of academic year for educators; a highly publicized fatal episode of anaphylaxis increases public awareness.
Key messages: Anaphylaxis is a killer allergy. Promptly inject epinephrine, activate emergency medical services*. Place the patient on the back or in a
position of comfort with lower extremities elevated.
Adapted from references 69, 153, 166, 188 and 189.
*Transport of the patient to an emergency department.

TABLE XIV. Reasons for lack of randomized controlled trials in patients with anaphylaxis
Anaphylactic episodes are unpredictable.
Anaphylaxis commonly occurs in community settings (eg, home, restaurant, and school).
Baseline measurements of vital signs and oxygenation are often not available.
Symptoms and signs vary from one person to another and from one episode to another, even in the same person, with regard to time of onset after exposure to
trigger (minutes to hours), body organ systems involved, severity, and duration.
Symptoms sometimes resolve spontaneously because of endogenous production of epinephrine, endothelin I, and angiotensin II.
Randomized placebo-controlled trials would be unethical for epinephrine, although randomized placebo-controlled trials of H1-antihistamines, H2-
antihistamines, and glucocorticoids might be conducted in the future.
Rarely, even with prompt and optimal treatment and monitoring, anaphylaxis can be fatal.

Adapted from reference 200.

office or clinic where allergen skin tests or allergen challenge/
provocation tests are performed or allergen-specific immunotherapy,
anti-IgE antibody injections or vaccine injections are given, it is
important to develop and rehearse an anaphylaxis management
plan, train the staff, and ensure availability of essential medica-
tions (within expiry date), as well as essential supplies and
equipment.195
The basic principles of anaphylaxis management in a health
care facility include rapid assessment of the patient’s airway,
breathing, circulation, and orientation/mentation; examination of
the skin; and estimation of body weight/mass. Initial treatment
involves discontinuing exposure to the trigger, if relevant (eg,
discontinuing administration of an intravenous medication or
biological agent), and then prompt and simultaneous intramus-
cular injection of epinephrine in a first-aid dose of 0.01 mg/kg to a
maximum adult dose of 0.5 mg, calling for help (either a
resuscitation team or 911/emergency medical services, whichever
is appropriate), and placing the patient on the back or in a position
of comfort with the lower extremities elevated.154,155,166,195 Ad-
ministration of supplemental oxygen by face mask at a rate of
at least 6 to 8 L/min, airway management, and insertion of 1 or
more large-bore (no. 14 or 16) needles or intravenous catheters
for infusion of large volumes of fluid, such as 0.5 to 1 L of
0.9% (isotonic) saline in 5 to 10 minutes to an adult, should be
performed if needed.154,155,163,195 Most anaphylaxis guidelines
recommend administration of an adjunctive medication such as
an H1-antihistamine, a nebulized b2-adrenergic agonist, and a
glucocorticoid154,155,163-166 and some also recommend an H2-
antihistamine.163
It has also been suggested that epinephrine and other vaso-
pressors should be administered intravenously only by physicians
who are trained, experienced, and equipped to administer these
potent medications effectively and safely; that is, to titrate the rate
of infusion (preferably by using an infusion pump), according to
J ALLERGY CLIN IMMUNOL
VOLUME 125, NUMBER 2
the patient’s hemodynamic response assessed by means of
continuous, noninvasive cardiac and blood pressure monitoring
and pulse oximetry.154,155 If it is used, intravenous epinephrine
should only be given by slow infusion (not a bolus) of a dilute so-
lution, 0.1 mg/mL (1:10,000) that is appropriate for intravenous
use, and not the concentrated 1 mg/mL (1:1,000) dilution that is
appropriate for intramuscular injection.154 Physician confusion
between dilute and concentrated epinephrine solutions potentially
leads to dosing errors and fatality.196 Existing studies do not per-
mit a conclusion with regard to whether any one vasopressor is su-
perior to another in preventing mortality in critically ill patients
with shock.197 Even in the hands of intensive care specialists,
use of intravenous vasopressors might not improve outcomes
and might increase fatality rates.198,199
FUTURE DIRECTIONS IN THE PHARMACOLOGIC
MANAGEMENT OF ANAPHYLAXIS
Recommendations for the treatment of acute anaphylactic epi-
sodes are based on expert opinion rather than on randomized
controlled trials in patients experiencing anaphylaxis at the time of
the study. The reasons for lack of randomized controlled trials of
pharmacologic interventions in anaphylaxis are summarized in Table
XIV.200
It is important to note that the evidence base for epinephrine
injection in the treatment of anaphylaxis is stronger than the
evidence base supporting the use of H1-antihistamines, H2-anti-
histamines, or glucocorticoids in anaphylaxis.160,165,183,185 Rec-
ommendations for prompt epinephrine injection are based on
fatality studies, epidemiologic studies, observational studies,
nonrandomized controlled studies in patients actually experienc-
ing anaphylaxis, randomized controlled studies in patients not ex-
periencing anaphylaxis at the time of the study, in vitro studies,
and studies in animal models.157-160,200
The World Health Organization (www.who.int) and the World
Allergy Organization,159 as well as all anaphylaxis guide-
lines,154,155,163-165 are in universal agreement that epinephrine in-
jection is fundamentally important in anaphylaxis management.
Placebo-controlled trials of epinephrine are therefore clearly un-
ethical. Recommendations for the maximum initial dose of epi-
nephrine or the route of injection differ among the guidelines,
however, and in the future, it might be possible to conduct ran-
domized trials comparing different first-aid epinephrine doses
or different routes of injection.200
In contrast to the consensus about epinephrine, there is no
consensus among published anaphylaxis guidelines with regard to
the use of H1-antihistamines, H2-antihistamines, or glucocorti-
coids in the treatment of anaphylaxis. Many different H1-antihis-
tamines in a variety of dose regimens are recommended.183
Several different glucocorticoids in a variety of dose regimens
are recommended.185 H2-antihistamines are not mentioned in
most guidelines.165 In the future, it might therefore be possible
to conduct randomized placebo-controlled trials of these medica-
tions in acute anaphylaxis episodes.200
If randomized controlled trials are conducted, in addition to the
intervention being tested, it will be critically important to take
rigorous appropriate precautions to ensure that all patients have
prompt, optimal, standard-of-care treatment with epinephrine
injections, are placed in the recumbent position or a position of
comfort with lower extremities elevated; and have appropriate
treatment with supplemental oxygen, airway management, and
SIMONS S177
high-volume intravenous fluid resuscitation, as well as continu-
ous noninvasive monitoring of heart rate, blood pressure, and
oxygenation.154,155,163,164,166,190,195
The assistance of Ms Lori McNiven is gratefully acknowledged.
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